Antibody–drug conjugates (ADCs) harness the highly specific targeting capabilities of an antibody to deliver a cytotoxic payload to specific cell types. This review summarises the advances made in the construction of homogenous ADCs.

Stapled peptides have great potential as modulators of protein–protein interactions (PPIs). However, there is a vast landscape of chemical features that can be varied for any given peptide, and identifying a set of features that maximizes cellular uptake and subsequent target engagement remains a key challenge. Herein, we present a systematic analysis of staple functionality on the peptide bioactivity landscape in cellular assays. Through application of a “toolbox” of diversified dialkynyl linkers to the stapling of MDM2-binding peptides via a double-click approach, we conducted a study of cellular uptake and p53 activation as a function of the linker. Minor changes in the linker motif and the specific pairing of linker with peptide sequence can lead to substantial differences in bioactivity, a finding which may have important design implications for peptide-based inhibitors of other PPIs. Given the complexity of the structure–activity relationships involved, the toolbox approach represents a generalizable strategy for optimization when progressing from in vitro binding assays to cellular efficacy studies.

An electrophile-bearing linker was developed for the generation of a stapled peptide covalent inhibitor of MDM2 via a two-component CuAAC peptide stapling.

Photoisomerization of diarylethene-modified peptides changes the thermodynamics of their binding to MDM2: the “closed” photoisomers bind largely due to a high negative enthalpy, whereas the “open” forms bind better due to a more favourable entropy.

A functionalisable divinyltriazine linker was developed for two-component peptide stapling and macrocyclisation of cysteine residues.